9-(2, 3-dihydroxypropylaminoethylamino)-acridines and their preparation



Patented Aug. 4, 1953 UNITED STATES PATENT OFFICE.

9 (2,3 DIHYDROXYPROPYLAMINOETHYL AMINO) -ACRIDIN ES AND THEIR PREP-ABATION Alexander R. Surrey and Robert K. Bair, Albany, N. Y., assignorsto Sterling Drug Inc., New York, N. Y., acorporatlon of Delaware NoDrawing. Application September 5, 1951,

Serial No. 245,252

14.0laims. 1

This invention relates to 9-(2,3-dihydroxypropylaminoethylamino)-acridine's.

These acridine compounds have been found to possess usefulchemo-therapeutic properties, especially as anthelmintic agents.

The acridines of the invention have the formula NHCHiCHaNHCHaCHaOHOHiOHwhere R is a lower alkoxy radical or hydrogen and R1 is halogen orhydrogen. R, when designating a lower alkoxy radical has preferably oneto six carbon atoms, encompassing such radicals as methoxy, ethoxy,n-propoxy, n-butoxy, isobutoxy, 2-butoxy, n-amoxy, n-hexoxy, and thelike. R1, when designating halogen, comprehends chloro, bromo, iodo orfiuoro.

The compounds having the above formula can be prepared preferably byheating amixture of phenol and the appropriate 9-haloacridinetoaminoethylamino)acridines of the invention can be prepared by directlyheating the appropriate 9-halo-acridine with N-(2,3-dihydroxypropyl)ethylenediamine, without first reacting the former compound with phenol.

The intermediate N (2,3 dihydroxypropyl) ethylenediamine can be preparedby reacting ethylenediamine with either glycidol orglycerolalphachlorohydrin.

The 9-(2,3dihydroxypropylaminoethylamino) acridines of the invention aretherapeutically active whether employed inthe form of their free basesor in the form of their salts with relatively non-toxic organic orinorganic acids. These salts can be prepared by treating the appropriate9 (2,3 dihydroxypropylaminoethylamino acridine described above with'theap- In another run, following the procedure 'de propriate acid. Inpracticing the invention, it has been found convenient to isolate the,com-- pounds in, the. form of, their. hydrochlorides. However, otheracid addition. salts are within thescope of the invention. Suchadditional saltsqine.

clude the hydrobromides, hydroiodides, sulfates, phosphates, citrates,sulfamates, tartrates, succinates, acetates, benzoates, oleates, and thelike;

The following examples. further: illustrate specific embodiments of theinvention.

- EXAMPLE 1- A. N-(2,3'-dihydromypropyl) ethylenediamine Thisintermediatediamine was prepared by re-- acting ethylenediamine witheither glycidolor.

glycerol-alpha-chlorohydrin as illustrated; in thefollowing paragraphs.

19.5 g. of glycidol (also called epihydrin alcohol, 2,3 epoxy 1 propanolor glycide) was.

added dropwise with stirring to g. of ethyl-: enediamine at 70 -80 C.over a period of ninety minutes. ethylenediamine was removed by,distillation in vacuo and the residue fractionated. There was; thusobtained 15 g. of product, B. P. 156? C. at. 0.25 micron,whichsolidified. This solid was re-' crystallized withpdifficulty fromisopropanole ether yielding, N (2,3 dihydroxypropyllethyle enediamine,M. P. 57-70 C.

Anal-Caled. for C5H14N202; NAP, Found: NAP, 19.74.

NAP stands for basic nitrogen as determined b the method of Toennies andCallan, J. Biol. Chem. 12 259- The picrate was prepared. It melted at196- 198 C; (corn) with decomposition.

Anal. Calcd. for "C17H20NsO16; Found: NAP, 4.83.

To a stirred solution containing 54 g. of potas- NAP, 4.73.

"sium hydroxide and 400 gyof ethylenediamine- 65 g. (50%), B. P; 170 C.at 0.2 mm. It was. found best to distill the product'as'rapidly as.possible. Other samples of this product were collectedat 156-158? C. at0.3 mm. The product.

solidifies on standing.

After standing overnight, the excess After recovering the 3 scribed inthe immediately preceding paragraph, a. yield of 52.7 g. ofN-(2,3-dihydroxypropyl) ethylenediamine was obtained when thetemperature of the mixture of potassium hydroxide and ethylenediaminewas kept at 35-40 C. during the addition of theglycerol-alpha-chlorohydrin.

B. 9- (2,3-dihydroxypropylaminoethylamino) Z-methoxyacridinedihydrochloride A mixture of 17 g. of 9-chloro-2-methoxyacridine and 70g. of phenol was heated with stirring for fifteen minutes on a steambath. To the resulting mixture containing 9-phenoxy-2- methoxyacridinehydrochloride wasadded 13 g. of N-(2,3-dihydroxypropyl) ethylenediamine,and heating and stirring were continued for another two hours. Thereaction mixture was poured with stirring into 300 cc. of acetonecontaining,

19 cc. of concentrated hydrochloric acid. The solid which separated wascollected, triturated with hot acetone, and recrystallized from 95%ethanol, yielding 20 g. of the product, 9-(2,3-dihydroxypropylaminoethylamino) 2 methoxyacridine in the form of itsdihydrochloride, M. P. 196.8-202.2 C. (corn).

Anal.Calcd. for C19H23N3O32HC12 Cl, 17.11; N, 10.14. Found: Cl, 17.03;N, 10.02.

N stands for total nitrogen as determined by the Dumas method.

Following the above procedure but without the use of phenol and thefifteen minute heating period, i. e., reaction of9-chloro-2-methoxyacridine directly with N (2,3 dihydroxypropyD-ethylenediamine, the same product,9-(2,3-dihydroxypropylaminoethylamino) 2 methoxyacridineclihydrochloride, can be obtained.

When the foregoing procedures are followed but using, in place of9-chloro-2-methoxyacridine, 9-bromoacridine (and concentratedhydrobromic acid in place of the hydrochloric acid), 9-chlor0-4-methoxyacridine, 9-chloro-3-ethoxyacridine, 9- chloro 2isobutoxyacridine and 9 chloro- 2-n-hexoxyacridine, there is obtained,respectively, 9- (2,3-dihydroxypropylaminoethylamino) acridinedihydrobromide, 9-(2,3-dihydroxypropylaminoethylamino) 4 methoxyacridinedihydrochloride, 9 (2,3 dihydroxyproplyaminoethylamino) 3 ethoxyacridinedihydrochloride, 9 (2,3 dihydroxypropylaminoethylamino) 2-isobutoxyacridine dihydrochloride and9(2,3-dihydroxyproplyaminoethylamino) 2 nhexoxyacridine.dihydrochloride.

EXAMPLE 2 6-chl0r09- 2,3 -dihydroatypropylaminoethylamino)-2-methoxyacridine dihydrochloride A mixture of 13.9 g. of6,9-dichloro-2-methoxyacridine and 45 g. of phenol was heated withstirring on a steam bath for fifteen minutes. To the resulting mixturecontaining 6-chloro-2- methoxy-Q-phenoxyacridine hydrochloride was added8.4 g. of N-(2,3-dihydroxypropyl) ethylenediamine, and heating andstirring were continued for two hours. The reaction mixture was pouredwith stirring into 150 cc. of acetone containing 12.5 cc. ofconcentrated hydrochloric acid. The yellow solid which separated wascollected, triturated with hot acetone and recrystallized from waterwith the addition of some sodium chloride, yielding 12 g. of theprdouct, 6- chloro 9 (2,3 dihydroxypropylaminoethylamino) 2methoxyacridine dihydrochloride, M. P. 207.4208.4j C. (corn).

'4 Anal.Calcd. for C19H22C1N3O32HC1; Cl, 23.72; N. 9.36. Found: C1,23.72; N, 9.30.

mide, 5 chloro 9 (2,3 dihydroxypropylamino'ethylamino) 2 -npropoxyacridine dihydrochloride, 4 n butoxy 7 chloro 9 -(2,3-dihydroxypropylaminoethylamino) acridine dihydrochloride and 6 chloro 9(2,3-dihydroxypropylaminoethylamino) 2 n hexoxyacridine dihydrochloride.

EXAMPLE 3 3-chZoro-9- 2,3 -dihydroxypropylaminoethylm mino) acridinedihydrochloride A mixture of 27.5 g. of 3,9-dichloroacridine and 75 g.of phenol was heated with stirring on a steam bath for fifteen minutes.To the resulting mixture containing 3-chloro-9-phenoxyacridinehydrochloride was added 13.5 g. of N- (2,3-dihydroxypropyl)ethylenediamine, and heating and stirring were continued for twoadditional hours. The reaction mixture was poured into 300 cc. ofacetone containing 22 cc. of concentrated hydrochloric acid. The productwas collected and washed with acetone; the yield was 27.5 g. (M. P.140-150" C.). One recrystallization from water to which sodium chloridehad been added and then from ethanol gave the product, 3 chloro 9 (2,3dihydroxypropylaminoethylamino)acridine in the form of itsdihydrochloride, melting at 179.7-181.7 C. (corn).

AnaZ.-Calcd. for C18H20C1N3O22HC1: Cl, 25.41; N, 10.04. Found: Cl,25.22; N, 10.17.

When the above procedure was followed but using, in place of3,9-dichloroacridine, 2,9-dichloroacridine, 4,9-dichloroacridine,3,9-dibromoacridine (and concentrated hydrobromic acid in place of thehydrochloric acid) and 9-chloro- 3-iodoacridine, there is obtained,respectively, 2- chloro 9 (2,3 dihydroxypropylaminoethylamino) acridinedihydrochloride, 4- chloro 9 (2,3- dihydroxypropylaminoethylamino)acridine dihydrochloride, 3 bromo 9 (2,3 dihydroxypropylaminoethylamino)acridine dihydrobromide and 3 iodo 9 (2,3dihydroxypropylaminoethylamino) acridine dihydrochloride.

What is claimed is:

l. A 9 (2,3 dihydroxypropylaminoethylamino)acridine having the formulawhere R is a member of the group consisting of hydrogen and a loweralkoxy radical and R1 is a member of the group consisting of hydrogenand halogen. I

2. A 2-alkoxy-6-ha1o-9-(2,3 --dihydroxypropylaminoethylamino) acridinehaving the formula NHCHzOHzNHCHzCHOHCHaOH where R is a lower alkoxyradical and R1 is halogen.

3. A 2-alkoxy 9 (2,3dihydroxypropylaminoethy1amino acridine having theformula ITIHCHICHQNHOHzCHOHCHQOH where R is a lower alkoxy radical.

4. A 3-ha1o-9-(2,3-dihydroxypropylaminoethy1amino acridine having theformula NHCHzOHzNHCHgCHOHOHzOH A OW/G where R is a member of the groupconsisting of hydrogen and a lower alkoxy radical and R1 is a member ofthe group consisting of hydrogen and halogen, the step which comprisesheating a member of the group consisting of the corresponding9-haloacridine and 9-phenoxyacridine hydrohalide with N-(2,3-dihydroxypropyl) ethylenediamine.

9. In the process of preparing a 2-alkoxy-6- ha1o-9-(2,3dihydroxypropylaminoethylamino) acridine having the formulaNHCHACHINHCHzCHOHCHiOH where R is a lower alkoxy radical and R1 ishalogen, the step which comprises heating the corresponding 2alkoxy-6-ha1o-9-phenoxyacridine monohydrochloride with N (2,3dihydroxypropyl) ethylenediamine.

10. In the process of preparing a 2-alkoxy-9- (2,3dihydroxypropylaminoethylamino) acridine having the formulaNHGHaCHzNHCHgCHOHCHzOH where R is a lower alkoxy radical, the step whichcomprises heating the corresponding Z-alkoxy-Q- phenoxyacridinehydrochloride with N-(2,3-dihydroxypropyl) ethylenediamine.

11. In the process of preparing a 3-ha1o-9- (2,3dihydroxypropylaminoethylamino) acridine having the formulaNHOHzOHzNHOHzCHOHCHzOH where R1 is halogen, the step which comprisesheating a. 3-halo-9-phenoxyacridine hydrochloride withN-(2,3-dihydroxypropyl)ethylenediamine.

12. In the process of preparing 9- (2,3-dihydroxypropylaminoethylamino 2methoxyacridine having the formula NHOHzCHzNHOHzOHOHCHzOH CHaO- the stepwhich comprises heating 2-methoxy-9- phenoxyacridine hydrochloride withN-(2,3-dihydroxypropyl) ethylenediamine.

13. In the process of preparing 6-ch1oro-9-(2,3-dihydroxypropylaminoethylamino) -2-methoxyacridine having theformula NHCHnOHzNHOHzOHOHOHzOH CH3O- the step which comprises heating6-chloro-2- methoxy-Q-phen0xyacridine hydrochloride with N-(2,3-dihydroxypropy1) ethylenediamine.

14. In the process of preparing 3-chloro-9- (2,3-dihydroxypropylaminoethylamino)acridine having the formulaNHCHzOHzNHOHzCHOHCHzOH the step which comprises heating 3-ch1oro-9-phenoxyacridine hydrochloride with N-(2,3-dihydroxypropyl)ethylenediamine.

ALEXANDER R. SURREY. ROBERT K. BAIR.

References Cited in the file of this patent UNITED STATES PATENTS NumberName Date 2,531,010 Surrey Nov. 21, 1950 2,531,011 Surrey Nov. 21, 19502,531,012 Surrey Nov. 21, 1950 OTHER REFERENCES McChesney et al., Proc.Soc. Exptl. Bial. Med,

V01. '72, pp 378-379 (1949)

1. A 9 - (2,3 - DIHYDROXYPROPYLAMINOETHYLAMINO) ACRIDINE HAVING THEFORMULA